The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment.

The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (padj≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.

NO EFFECT OF REAL-WORLD UNIVERSAL FACE MASKING ON POST-INTRAVITREAL INJECTION ENDOPHTHALMITIS RATE AT A SINGLE TERTIARY ACADEMIC CENTER.

PURPOSE: To determine whether universal masking during COVID-19 altered rate and outcomes of postinjection endophthalmitis. METHODS: Retrospective, single-site, comparative, cohort study. Eyes diagnosed with endophthalmitis within 4 weeks of intravitreal injection at the University of Michigan from August 1, 2012, to November 15, 2022, were identified. Cases were considered "masking" between March 15, 2020, and November 15, 2022. Endophthalmitis rate, visual acuity, and microbial spectrum were investigated. RESULTS: There were 20 postinjection endophthalmitis cases out of 72,194 injections (0.028%; one in 3,571 injections) premasking and 10 of 38,962 with universal masking (0.026%; one in 3,846 injections; odds ratio 0.9; 95% [confidence interval]: 0.4-2.0). Referral from the community was unchanged with 32 cases referred premasking (0.35 cases/month) and 10 cases with masking (0.31 cases/month). Presenting mean the logarithm of the minimum angle of resolution visual acuity with masking of all postinjection endophthalmitis cases trended worse (2.35 ± 0.40) compared with premasking (2.09 ± 0.48; P = 0.05) with light perception visual acuity more common with masking (31.6% vs. 10.9%, P = 0.06). There was no delay in time from procedure to initial treatment ( P = 0.36), no difference in the rate of initial treatment with tap and inject (T/I), and similar positive-culture rates ( P = 0.77) between the cohorts. Visual acuity after 30 days of follow-up was clinically unchanged (∼20/500 vs. 20/400; P = 0.59). CONCLUSION: Universal masking had no effect on postinjection endophthalmitis rate or on the rate of culture-positive cases. Although presenting visual acuity appeared worse with masking, this was not statistically significant, and current treatment paradigms resulted in similar visual outcomes.

Autophagy activation and photoreceptor survival in retinal detachment.

We assess the effect of autophagy inhibition on photoreceptor (PR) survival during experimental retinal detachment (RD) and examine the and examine the relationship between autophagy and the expression of glycolytic enzymes HK2 and PKM2 in the retina. We find that inhibiting autophagy by genetic knock out of the autophagy activator Atg5 in rod PRs resulted in increased apoptotic and necroptotic cell death during RD, demonstrated by elevated terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, caspase 8 activity, transcript levels of Fas receptor and RIPK3 as compared to controls. The absence of autophagy in rods resulted in downregulation of hexokinase 2 and pyruvate kinase muscle isozyme 2 levels. More than 460 proteins were identified by mass spectroscopy in autophagosomes isolated from detached retinas compared with less than 150 proteins identified in autophagosomes from attached retinas. Among various cellular compartments, proteins from cytoskeleton, cytoplasm and intracellular organelles constituted a large portion of increased autophagosome contents. These proteins represent numerous biological processes, including phototransduction, cell-cell signaling, metabolism and inflammation. Our findings suggest that competent autophagy machinery is necessary for PR homeostasis and improving PR survival during periods of nutrient deprivation.

Antimicrobial guide to posterior segment infections.

PURPOSE: This review article is meant to serve as a reference guide and to assist the treating physician in making an appropriate selection and duration of an antimicrobial agent. METHODS: Literature review. RESULTS: Infections of the posterior segment require prompt medical or surgical therapy to reduce the risk of permanent vision loss. While numerous options exist to treat these infections, doses and alternative therapies, especially with contraindications for first-line therapy, are often elusive. Antimicrobial agents to treat posterior segment infections can be administered via various routes, including topical, intravitreal, intravenous, and oral. CONCLUSIONS: Although there are many excellent review articles on the management of endophthalmitis, we take the opportunity in this review to comprehensively summarize the appropriate antimicrobial regimen of both common and rare infectious etiologies of the posterior segment, using evidence from clinical trials and large case series.

Temporally independent association of multiple evanescent white dot syndrome and optic neuritis.

PURPOSE: To describe three patients that developed temporally distinct episodes of optic neuritis and multiple evanescent white dot syndrome (MEWDS). METHODS: We retrospectively reviewed the medical records and imaging studies of three women evaluated at a tertiary referral center for both optic neuritis and MEWDS. RESULTS: Three otherwise healthy women, aged 17, 36, and 41, developed temporally separated episodes of optic neuritis and MEWDS. The time periods between the two events were 3, 48, and 60 months, and in two of the three cases, the optic neuritis event preceded the episode of MEWDS. No patient endorsed prodromal flu-like symptoms prior to developing vision loss. The mean presenting visual acuities were better with the optic neuritis episode (LogMAR 0.360, Snellen 20/46) than with retinal event (LogMAR 0.684, Snellen 20/97). All three patients had improvement in vision, with mean visual acuity of 20/29 (LogMAR 0.165) at last follow-up. One patient later developed idiopathic noninfectious posterior uveitis and another developed multiple sclerosis requiring treatment. CONCLUSION: While a rare association, patients can develop both optic neuritis and MEWDS within the same eye at different time points. It is unknown whether such patients are at even higher risk of developing systemic autoimmune disease than are patients with either MEWDS or optic neuritis alone.

Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa.

Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma.

BACKGROUND: Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma. METHODS: Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Faslpr) mice and WT C57BL/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2 µg/1 µl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28 days post-microbead injection, Brn3a-stained RGCs and paraphenylenediamine (PPD)-stained axons were analyzed. The effects of ONL1204 on retinal microglia activation and the expression of inflammatory genes were analyzed by immunostaining of retinal flatmounts and quantitative PCR (qPCR). RESULTS: Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28 days post-microbead injection, the RGC and axon counts from microbead-injected Faslpr mice were equivalent to saline-injected (no IOP elevation) controls. Treatment with ONL1204 also significantly reduced RGC death and loss of axons in microbead-injected WT mice when compared to vehicle-treated controls, even when administered after IOP elevation. Confocal analysis of Iba1-stained retinal flatmounts and qPCR demonstrated that ONL1204 also abrogated microglia activation and inhibited the induction of multiple genes implicated in glaucoma, including cytokines and chemokines (GFAP, Caspase-8, TNFα, IL-1ß, IL-6, IL-18, MIP-1α, MIP-1ß, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3). CONCLUSIONS: These results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation. Moreover, Fas signaling contributes to the pathogenesis of glaucoma through activation of both apoptotic and inflammatory pathways.

A platform for assessing outer segment fate in primary human fetal RPE cultures.

The daily shedding and renewal of photoreceptor outer segments (OS) is critical for maintaining vision. This process relies on the efficient uptake, degradation, and sorting of shed OS material by the retinal pigment epithelium (RPE). Poor OS degradation has been linked to retinal degenerations such as Stargardt disease and may contribute to macular degeneration. While primary human fetal RPE cultures have emerged as a valuable model of in vivo human RPE function, surprisingly few studies have utilized the model for tracking the degradation and fate of OS components in the RPE. Here, we establish an improved platform for studying this topic by modifying existing protocols and creating new methods. Our human fetal culture model facilitates studies of RPE secretion in response to OS ingestion, preserves RPE differentiation and polarization during live-cell imaging of OS phagocytosis, and minimizes costs. We optimize Mer tyrosine kinase-dependent OS phagocytosis assays specifically in human fetal cultures and provide a simple and accurate method for measuring total OS consumption by the RPE. Finally, we utilize chemical transfection, dextran labeling, and immunocytochemistry to evaluate key players in OS degradation, including lysosomes and autophagy proteins. To facilitate quantification of autophagy vesicles, we develop customized image analysis macros in the Fiji/ImageJ software environment. These protocols will facilitate a broad range of studies in human fetal RPE cultures aimed at determining the ultimate fate of OS components after ingestion, a critical step in understanding the pathogenesis of numerous retinal diseases.

Retinal neuroprotection: current strategies and future directions.

PURPOSE OF REVIEW: Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders. Currently, there are no commercially available treatments to prevent photoreceptor cell loss and preserve vision, and there is a critical unmet need for neuroprotective modalities to improve photoreceptor survival in a multitude of retinal disorders. This review summarizes the literature published on this topic in the last 18 months. RECENT FINDINGS: A plethora of novel therapeutic modalities for photoreceptor neuroprotection have recently been examined in clinical trials for age-related macular degeneration, inherited retinal dystrophies, and macular telangiectasia type 2. These modalities include agents that target the complement pathway, stem cells, gene therapies, and neurotrophic factors. Additionally, improved understanding in the metabolic signals that regulate photoreceptor survival and function may ultimately identify targets for developing novel neuroprotective agents in a multitude of retinal disorders. SUMMARY: Retinal neuroprotection is the next frontier in ophthalmic disease, and the discovery of novel neuroprotective strategies will fill a critical unmet need. Although the clinical utility of existing neuroprotective therapies is still quite limited, we are cautiously optimistic in light of the recent successes described in this review as well as other promising developments.

NOVEL CLASSIFICATION SYSTEM FOR COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM.

PURPOSE: To develop an anatomical classification scheme for combined hamartoma of the retina and retinal pigment epithelium (RPE) and specify recommendations for follow-up interval. METHODS: Retrospective review of patients with combined hamartoma of the retina and RPE examined during a 7-year period (2008-2015). The clinical presentation, fundus examination, and optical coherence tomography were analyzed. RESULTS: Lesions were classified based on location, fundus features, and optical coherence tomography findings. Lesion location: macular/peripapillary-Zone 1; mid-periphery-Zone 2; and far periphery-Zone 3. Associated fundus findings: no retinal traction-Stage 1; retinal traction and/or retinoschisis-Stage 2; and retinal detachment-Stage 3. Optical coherence tomography findings: epiretinal component only-A; partial retinal involvement-B; and complete retinal and RPE involvement-C. Complete ophthalmologic evaluation is recommended at least every 6 months for patients younger than 12 years, with more frequent follow-up in patients with: lesions in the macula/peripapillary (Zone 1) or with retinal traction, retinoschisis, or retinal detachment (Stage 2 and 3). Surgical intervention is recommended in patients with vision loss secondary to macular traction or retinal detachment. CONCLUSION: A new clinical classification system is proposed for evaluating and managing patients with combined hamartoma of the retina and RPE. The zone and stage of combined hamartoma of the retina and RPE lesion will assist in determining follow-up interval and surgical intervention. Application of a uniform classification scheme will facilitate assessment and comparison of findings across different studies.

TESTOSTERONE SUPPLEMENTATION AND RETINAL VASCULAR DISEASE.

PURPOSE: To determine whether testosterone supplementation is associated with retinal artery occlusion (RAO) or retinal vein occlusion (RVO). METHODS: Retrospective matched cohort study using data from a large national U.S. insurance database. The testosterone cohort consisted of all male patients who filled a prescription for testosterone from 2000 to 2013. Five controls were matched on age (±3 years), sex, race, and similar time in plan (±3 months) for every exposed patient. Exclusion occurred for <2 years in the plan, <1 eye care visit, medications known to affect androgen levels, and systemic diseases associated with occlusions or increased testosterone. Cox proportional hazard regression assessed the hazard of a new diagnosis of RAO or RVO while controlling for age, race, diabetes mellitus, and hypertension. RESULTS: A total of 35,784 incident testosterone users were compared with 178,860 matched controls. Ninety-three (0.3%) RAOs and 50 (0.1%) RVOs were found in the testosterone cohort and contrasted with 316 (0.2%) RAOs and 232 (0.1%) RVOs in the control group. After multivariate analysis, testosterone supplementation significantly increased the hazard of RAO (hazard ratio: 1.43, 95% confidence interval: 1.12-1.81, P = 0.004), but not of RVO (hazard ratio: 1.03, 95% confidence interval: 0.74-1.42, P = 0.86). CONCLUSION: Although the incidence of RAO and RVO is low in users of testosterone, supplementation therapy is associated with an increased hazard of RAO, but apparently not of RVO.

Pharmacotherapies for Retinal Detachment.

Retinal detachment is an important cause of visual loss. Currently, surgical techniques, including vitrectomy, scleral buckle, and pneumatic retinopexy, are the only means to repair retinal detachment and restore vision. However, surgical failure rates may be as high as 20%, and visual outcomes continue to vary secondary to multiple processes, including postoperative cystoid macular edema, epiretinal membrane formation, macular folds, and, ultimately, photoreceptor death. Therefore, pharmacotherapies are being sought to aid the success rates of modern surgical techniques and reduce or slow the degeneration of photoreceptors during retinal detachment. This review discusses potential therapeutic avenues that aid in retinal reattachment, reduce the rate of retinal redetachment by limiting proliferative vitreoretinopathy, and protect against photoreceptor cell death.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.

The Development of a Cat Model of Retinal Detachment and Re-attachment.

We present an optimized surgical technique for feline retinal detachment which allows for natural re-attachment, reduces retinal scarring and vitreal bands, and allows central placement of the detachment in close proximity to the optic nerve. This enables imaging via Optical Coherence Tomography (OCT) and multifocal electroretinography (mfERG) analysis. Ideal detachment conditions involve a lensectomy followed by a three-port pars plana vitrectomy. A 16-20 % retinal detachment is induced by injecting 8 % C3F8 gas into the subretinal space in the central retina with a 42G cannula. The retinal detachment resolves approximately 6 weeks post-surgery. Imaging is enhanced by using a 7.5 and 20 diopter lens for OCT and mfERG fundus imaging, respectively, to compensate for the removed lens.

Hypoxia inducible factor 1α contributes to regulation of autophagy in retinal detachment.

Photoreceptor (PR) cells receive oxygen and nutritional support from the underlying retinal pigment epithelium (RPE). Retinal detachment results in PR hypoxia and their time-dependent death. Detachment also activates autophagy within the PR, which serves to reduce the rate of PR apoptosis. In this study, we test the hypothesis that autophagy activation in the PR results, at least in part, from the detachment-induced activation of hypoxia-inducible factors (HIF). Retina-RPE separation was created in Brown-Norway rats and C57BL/6J mice by injection of 1% hyaluronic acid into the subretinal space. Retinas were harvested and assayed for HIF protein levels. Cultured 661W photoreceptor cells were subjected to hypoxic conditions and assayed for induction of HIF and autophagy. The requirement of HIF-1α and HIF-2α in regulating photoreceptor autophagy was tested using siRNA in vitro and in vivo. We observed increased levels of HIF-1α and HIF-2α within 1 day post-detachment, as well as increased levels of BNIP3, a downstream target of HIF-1α that contributes to autophagy activation. Exposing 661W cells to hypoxia resulted in increased HIF-1α and HIF-2α levels and increase in conversion of LC3-I to LC3-II. Silencing of HIF-1α, but not HIF-2α, reduced the hypoxia-induced increase in LC3-II formation and increased cell death in 661W cells. Silencing of HIF-1α in rat retinas prevented the detachment-induced increase in BNIP3 and LC3-II, resulting in increased PR cell death. Our data support the hypothesis that HIF-1α, but not HIF-2α, serves as an early response signal to induce autophagy and reduce photoreceptor cell death.

Stellate nonhereditary idiopathic foveomacular retinoschisis.

PURPOSE: To describe a new classification of stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR). DESIGN: Retrospective case series and literature review. PARTICIPANTS: A total of 17 patients from 5 institutions. METHODS: Detailed case history, multimodal imaging, and genetic testing were reviewed for patients with macular schisis without a known predisposing condition. Patients with a stellate appearance centered on the fovea with correlating confirmed expansion of the outer plexiform layer (OPL) by optical coherence tomography (OCT) were included. Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or advanced glaucomatous optic nerve changes. MAIN OUTCOME MEASURES: Clinical features, anatomic characteristics, and visual acuity. RESULTS: A total of 22 eyes from 16 female patients and 1 male patient with foveomacular schisis were reviewed from 5 institutions. Initial visual acuity was ≥ 20/50 in all eyes (mean, 20/27), but visual acuity in a single eye decreased from 20/20 to 20/200 after the development of subfoveal fluid. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to >5 years. CONCLUSIONS: In this largest known series of patients with SNIFR, all patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (≥ 20/40) except in a single patient in whom subretinal fluid developed under the fovea.

Retinal cell death and current strategies in retinal neuroprotection.

PURPOSE OF REVIEW: Retinal cell death is the main cause of vision loss in many blinding conditions. Research on the basics of how and why retinal cells die in different diseases provides insights into the development of treatment strategies to prevent or reverse this loss. This review summarizes the literature published on this topic in the last year. RECENT FINDINGS: Apoptosis is generally considered the main pathway by which retinal cells die in response to a range of noxious stimuli. However, inhibiting apoptosis does not completely prevent retinal cell death, as many enter programmed necrosis or necroptosis. Many novel ways of inhibiting apoptosis and necrosis, including blockage of the Fas receptor, neuroprotective peptides and antioxidants, continue to be investigated. Also, additional pathways including autophagy and inflammation are being examined on how they contribute to the loss of retinal cells in different disease models. SUMMARY: With more knowledge of how retinal cells die, further advances are being made in prolonging the cell survival. However, even as basic science discoveries remain promising, clinical utility of neuroprotection is still quite limited at this time.

Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor.

Due to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases. We previously reported the activation of Fas-mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H, and demonstrated the protective effect of genetic Fas inhibition. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation, rate of PR cell death, retinal function, and the activation of immune cells in the retina were evaluated. In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) PRs, decreased caspase 8 activity, enhanced photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. Treatment with ONL1204 also reduced immune cell activation in the retinas of both rd10 and P23H mice. The protective effect of pharmacologic inhibition of Fas by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential therapeutic approach to preserve the retina in patients with IRD, regardless of the genetic underpinning.

Retinal Detachments after Open-Globe Injury: Risk Factors and Outcomes.

PURPOSE: To identify risk factors for retinal detachment (RD) after open-globe injury (OGI) and evaluate outcomes of RD repair after OGI. DESIGN: Case-control study. PARTICIPANTS: Overall, 769 patients presented with 786 OGIs, which were surgically managed with ≥ 30 days of follow-up. Of the 786 eyes, 223 developed RD, the other 551 served as controls, and RD status of 12 eyes was unknown. METHODS: A retrospective chart review was performed of all OGIs presented to the University of Michigan between 2000 and 2022. Multivariable regression identified risk factors for RD after OGI and predictors of poor vision after RD repair. Kaplan-Meier analysis estimated time from OGI to RD. MAIN OUTCOME MEASURE: Predictors of visual outcome after RD repair after OGI. RESULTS: After OGI, 223 (28.4%) of 786 eyes were diagnosed with RD, with > 73% diagnosed within a month. Predictors of RD include posterior injury (zone II vs. I odds ratio [OR], 1.60 [95% confidence interval {CI}, 1.04-2.46]; P = 0.0331; zone III vs. I OR, 2.29 [1.53-3.41]; P < 0.0001), vitreous hemorrhage (OR, 2.29 [1.54-3.1]; P < 0.0001), and presenting acuity worse than count fingers (CFs) (OR, 2.65 [1.69 - 4.16]; P < 0.0001). Retinal detachment repair took place in 142 of 223 eyes. The mean logarithm of minimal angle of resolution visual acuity (VA) improved from 2.3 ± 0.8 to 1.7 ± 0.9 after RD repair at 6-month follow-up, with 51.2% of eyes achieving CF or better vision. Single surgery anatomic success rate was 69.7% and final anatomic success was 88%. Predictors of vision worse than CF include history of ocular surgery (OR, 0.32 [0.11-0.94]; P = 0.039), proliferative vitreoretinopathy (PVR; OR, 0.39 [0.16 - 0.92]; P = 0.032), aphakia (OR, 0.25 [0.08 - 0.77]; P = 0.016), and redetachment (OR, 0.26 [0.1 - 0.63]; P = 0.003). CONCLUSIONS: Most RD occur within the first month after OGI. Patients with posterior injuries, vitreous hemorrhage, or poor presenting VA were more likely to develop RD after OGI. Anatomic success was achieved in the majority, as was final VA of CF vision or better. History of ocular surgery, PVR at time of repair, aphakia, and redetachment were risk factors for a poor outcome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.